Mild cognitive impairment (MCI) is a syndrome of cognitive impairment that is not significant enough to interfere with daily activities unlike dementia and does not hinder basic dairy life, but causes a memory loss of an important promise and difficulty in travelling to a first place, for example.
In an Initial stage of MCI, mild impairment of cognitive function is observed irrespective of the type of accumulated harmful proteins, but irreversible alteration of cranial nerve tissues has not occurred yet in many cases. On the other hand, in patients already suffering from dementia, such as dementia caused by cerebral amyloid angiopathy, frontotemporal dementia, Lewy body dementia, Alzheimer-type dementia, and dementia caused by Parkinson's disease, pathologically irreversible neurodegeneration is often observed.
MCI is not merely a previous stage of specific dementia, such as dementia caused by cerebral amyloid angiopathy, frontotemporal dementia, Lewy body dementia, Alzheimer-type dementia, cerebrovascular dementia, dementia caused by Parkinson's disease, and prion disease. In MCI patients, various pathological changes such as Lewy body change, progressive supranuclear palsy change, Alzheimer change, argyrophilic grain change, vascular disorder change are observed, and these changes are opposite to a single pathological change (see Non-patent Document 1).
As described above, MCI should be distinguished from various known types of dementia, and is actually considered as such. In a “Guidelines for Management of Dementia” (http://www.neurology-jp.org/guidelinem/nintisyo.html) published on the homepage of Japanese Society of Neurology, MCI is listed in parallel with general dementia, and is treated as a disease distinguished from dementia. To make a diagnosis of MCI, “the presence of a difficulty in daily activities”, “a decreased cognitive function”, and “the absence of a diagnosis of dementia” are checked, and then, the case is classified as amnestic MCI or non-amnestic MCI depending on the presence or absence of memory impairment, and is further segmented (see the guideline, chapter 4: Progress and Therapeutic Strategy, B. mild cognitive impairment, item CQ IV B-1, pp. 108-109).
An MCI patient may be able to remain in an MCI state, or may be converted to one of the above-mentioned types of dementia. Thus, even if a drug is statistically demonstrated to be effective for a specific dementia such as Alzheimer-type dementia, cerebrovascular dementia, Lewy body-type dementia, frontotemporal dementia, or dementia caused by Parkinson's disease, it is still unknown that the drug is effective for MCI. For this reason, if a diagnosis of MCI is made, since MCI can be converted to various types of dementia as described above, it is apparent that risk manage and MCI treatment at an early stage are preferable especially for elderly people of 65 years of age or more.
Many clinical trials have been actually conducted on known dementia therapeutic drugs in order to confirm an effect on MCI. However, the “Guidelines for Management of Dementia” above shows a result that an effectiveness on MCI patients is very limited or is not present with respect to donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl), which are well-known dementiatherapeutic drugs as acetylcholinesterase inhibitors. From this result, it is concluded that these drugs have no prophylactic effects of conversion from MCI to dementia or Alzheimer (see the guideline, chapter 4: Progress and Therapeutic Strategy, p. 115). This is also shown in Non-patent Document 2 (see especially item 3, p. 585).
The guideline also shows that in a randomized controlled trial (RCT) directed to postmenopausal women of 65 years of age or more without dementia, estrogen unexpectedly increased the risk of onset of dementia or MCI significantly (see the guideline, pp. 115-116, Item 2, Other Drugs (1)), and even administration of rofecoxib (an COX-2 inhibiter) of a nonsteroidal anti-inflammatory drug showed no prophylactic effects (see the guideline, p. 116, item 2, Other Drugs (2)). Regarding Ginkgo biloba and vitamin E that have been recently used as dementiatherapeutic drugs, an RCT directed to MCI patients shows a result that neither dementia prophylactic effect nor prophylactic effect against conversion to Alzheimer was obtained (see the guideline, p. 116, item 2, Other Drugs (3) and (4)). In addition, it is reported that vitamin E and donepezil do not affect conversion from MCI to Alzheimer (see Non-patent Document 3).
For the foregoing reasons, there is neither an effective drug for preventing conversion from MCI to dementia nor a technique or an agent effective for MCI treatment, and early development of prophylactic and therapeutic agent for MCI is needed.
Cilostazol is an antiplatelet drug marketed as a trade name “Pletal” from Otsuka Pharmaceutical Co., Ltd., and there are a large number of other generic drugs of the antiplatelet drug. Cilostazol inhibits thrombus formation and induces vasodilation. Thus, it is well known that cilostazol is used for treatment of cerebral infarction (see Non-patent Document 4), and protects vascular endothelia (see Non-patent Document 5) and improves bloodstream through vasodilation irrespective of endothelia (see Non-patent Document 6). In addition, it is also known that cilostazol reduces accumulation of amyloid β (hereinafter may simply referred to as “Aβ”) protein.
Applications of cilostazol to specific diseases are shown in several documents showing application for treatment of amyloid β protein inducible cognitive impairment and treatment of Alzheimer's disease (see Non-patent Document 7) and effectiveness for treatment of dementia (see Non-patent Document 8). It is also known that cilostazol inhibits amyloid β protein inducible memory impairment and oxidation stress (see Non-patent Document 9). Patent Document 1 shows that the use of cilostazol enables treatment of Alzheimer's disease. These documents, however, only examined therapeutic effects by using model animals, and demonstrated no therapeutic effects of cilostazol on humans.
On the other hand, Non-patent Document 10 describes that administration of cilostazol to Alzheimer's patients can reduce deterioration of cognitive function. However, no change is observed in mini-mental state examination (MMSE), and significant variations are found in other evaluations (ADAS-Jcog, WMS-R, and TMT-A) on cognitive function of Alzheimer's patients. Thus, administration of cilostazol to Alzheimer's patients hardly shows improvement. It is shown in the guideline, chapter II, p. 32 that MMSE is the most excellent screening test in a diagnosis of cognitive function. Non-patent Document 11 shows that combined administration of cilostazol and donepezil tends to improve MMSE scores in Alzheimer's patients. This effect, however, is not obtained by cilostazol alone.
That is, the effectiveness of cilostazol alone for treatment of MCI patients based on data has not been substantially shown yet. Although MCI is considered a previous state of various types of dementia and Alzheimer's disease, no effective therapeutic drugs have been found yet.
In the brain of a central nervous system, harmful proteins such as tau protein, synuclein protein, ubiquitinated protein, amyloid protein, and prion protein are accumulated and cause hypofunction of cranial nerves. However, only one of the harmful proteins is less likely to be accumulated in elderly persons. That is, multiple harmful proteins are accumulated in many cases, and the type and degree of this accumulation differ among individuals (see Non-patent Documents 1 and 12).
Such accumulation of harmful proteins are believed to cause cognitive impairment such as MCI. For example, accumulation of amyloid β is found in 60-70% of MCI patients (see Non-patent Document 13), and drainage thereof is considered to contribute to prevention and treatment of MCI.
One of drainage pathways commonly used for such harmful proteins is drainage through perivascular lymph drainage pathway (interstitial flow) (sec Non-patent Document 14), but neither a technique nor an agent for sufficiently activating the perivascular lymph drainage pathway (interstitial flow) has been found yet.